Mammals must combat infectious diseases throughout their entire lives in continuous fights for survival where failure to eliminate pathogens results in either chronic disease or death, depending on the infectious agent. Successful elimination of these pathogens and increased longevity increase the probability of combating spontaneously arising tumors that threaten survival unless they can be eliminated. Importantly, battles against these two adversaries must often be waged simultaneously and are limited by the capabilities of the affected individuals. Without question, one of the most important limitations on the ability to fight infectious agents and cancer is age with its debilitating effects on strength and flexibility. The responsibility for fighting pathogens and cancer falls to the innate and adaptive arms of the immune system which have evolved for the brute-force elimination of large numbers of infectious agents as well as the surgically precise identification and elimination of infected cells and cancers. Lymphoid cells that contribute these complementary functions are maintained within individual organisms with the resources that are available and that are affected by selective factors including age, history of infections, nutrition, and physical and mental strength. Therefore, the immune system must function within defined limitations. Competition must occur between populations of lymphoid cells for general resources and space but also within individual lymphocyte populations for signals and cytokines that are specific for maintenance and functions of those specific populations. Competition within the T cell compartment has been extensively documented, and both naive and memory T cell subpopulations are homeostatically maintained. The limits of T cell populations are further exemplified by the transient expansions and contractions associated with T cell responses to viruses where the end result is increased memory cell frequencies but negligible changes in population size. The fluctuations in sizes of responding T cell populations raise the question as to how the responses to recurring challenges develop over time through utilization of T cells that have already established themselves as effective responders and T cells that are newly differentiated and previously untested. Of course, the next logical question asks how these potentially contributing T cells expand and function when the T cell compartment is forced to sustain responses to other pathogenic viruses. This is particularly important for humans who are long-lived and the life-long targets of chronic and recurring acute infections. The studies proposed in this application are aimed at addressing these important issues with an experimental approach to directly evaluate the contributions of naive and memory T cells in sustaining responses to repeated antigenic challenges under relatively neutral conditions as well as conditions that stress the function, diversity, and regenerative capacity of the T cell compartment. PUBLIC HEALTH RELEVANCE: Humans immunologically respond to a wide variety of infectious diseases and vaccinations throughout their lives, and the abilities of individuals to respond to these stimuli are affective by selective factors that include age and history of infections. The experiments presented in this application are aimed at understanding how multiple encounters with foreign proteins stimulate responses of lymphocytes that are either unrestrained or stressed by aging and responses to infections.